NM_000380.4(XPA):c.368del (p.Leu123fs) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 2, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001233440.7

Allele description [Variation Report for NM_000380.4(XPA):c.368del (p.Leu123fs)]

NM_000380.4(XPA):c.368del (p.Leu123fs)

Gene:

XPA:XPA, DNA damage recognition and repair factor [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

9q22.33

Genomic location:

Preferred name:

NM_000380.4(XPA):c.368del (p.Leu123fs)

HGVS:

NC_000009.12:g.97689557del
NG_011642.1:g.12855del
NM_000380.4:c.368delMANE SELECT
NM_001354975.2:c.242del
NP_000371.1:p.Leu123fs
NP_001341904.1:p.Leu81fs
LRG_471t1:c.368del
LRG_471:g.12855del
NC_000009.11:g.100451837del
NC_000009.11:g.100451839del
NM_000380.3:c.368del
NR_027302.2:n.416del
NR_149093.2:n.416del

Protein change:

L123fs

Links:

dbSNP: rs778804405

NCBI 1000 Genomes Browser:

rs778804405

Molecular consequence:

NM_000380.4:c.368del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354975.2:c.242del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_027302.2:n.416del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_149093.2:n.416del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001406034	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27607234, 28492532
SCV003923879	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Nov 2, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001406034

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 20, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV003923879

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Nov 2, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical and molecular epidemiological study of xeroderma pigmentosum in China: A case series of 19 patients.

Zhou EY, Wang H, Lin Z, Xu G, Ma Z, Zhao J, Feng C, Duo L, Yin J, Yang Y.

J Dermatol. 2017 Jan;44(1):71-75. doi: 10.1111/1346-8138.13576. Epub 2016 Sep 8.

PubMed [citation]

PMID:: 27607234

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001406034.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 959994). This variant has not been reported in the literature in individuals affected with XPA-related conditions. This variant is present in population databases (rs778804405, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Leu123Cysfs*17) in the XPA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in XPA are known to be pathogenic (PMID: 27607234).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV003923879.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in a patient with lung adenocarcinoma (Lu et al., 2015); This variant is associated with the following publications: (PMID: 26689913)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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